The standard therapy for men with metastatic prostate cancer is to reduce tumor size by androgen ablation, either by bilateral orchiectomy or the use of luteinizing hormone-releasing hormone analogues. While many prostate cancer cells die in the absence of androgens, some cells are androgen-independent and do not require androgens for survival. With time, the surviving cells begin to grow aggressively. The result is that most men receiving this therapy develop recurrent tumors and die within two years. To improve the effectiveness of this therapy, we hypothesize that following androgen ablation therapy for the treatment of prostatic carcinoma, application of a regulated recombination system to target expression of diphtheria toxin (DT-A) to androgen independent cancer cells would be an effective way to arrest the development of recurrent tumors. We propose a strategy to use replicative-defective adenoviral vectors to deliver DT-A specifically to androgen-independent prostate cancer cells. The regulated expression of this highly toxic protein in cells will result in their death. We shall test the effectiveness of this approach in cultured human prostate cancer cells, in xenografts in mice developed from such cells, and in prostate tumors in a transgenic mouse model. We expect our investigations will lead to the development of a novel gene therapy for prostate cancer patients that will effectively arrest the development of recurrent tumors.